This application claims the benefit of U.S. provisional application 60/017,565, filed May 14, 1996.
The invention pertains to novel pyridinyl benzamide derivatives having drug and bio-affecting properties and to their preparation, pharmaceutical formulations and use. In particular, the invention concerns tri-substituted benzamides having a pyridine ring, with and without an alkyl linker, attached to the amide nitrogen. These compounds possess potent anticonvulsant properties that should make them useful in treating certain medical disorders.
The anticonvulsant drugs currently available in the United States have several shortcomings as therapeutic agents. About one of every three patients does not obtain significant relief from seizures and a number of side-effects accompany the therapeutic effects obtained. An underlying reason for the high incidence of side-effects is that most current anticonvulsant agents possess low therapeutic ratios. For this reason, new anticonvulsants, which may possess greater selectivity and less toxicity in a clinical population, are needed.
A large number of various benzamide derivatives are known and the use of many of them as medicinals has been disclosed.
A number of amino-substituted benzamides have been disclosed as anticonvulsant agents. In general, these disclosed compounds have structural formula 1, wherein Z is a substituted phenyl or phenylalkyl moiety. ##STR2##
For example, Robertson claims anticonvulsants, 2, in U.S. Pat. No. 4,684,748; ##STR3## and in U.S. Pat. No. 4,981,866, Beedle and Robertson claim the use of various mono-substituted benzamide derivatives, 3, as anticonvulsants. ##STR4## In formula 3, R.sup.1 can also be hydroxy, alkoxy and alkyl in addition to being substituted amino.
While a number of pyridinyl benzamide derivatives are known, they are not tri-substituted benzamides and have not been particularly disclosed for use as anticonvulsant agents. These known pyridinyl benzamide compounds conform to the general structural formula 4. In 4, R.sup.1 can be hydrogen, halogen, alkyl, alkoxy, amino and nitro; R.sup.2 is generally amino; ##STR5## and A is a chemical bond or an alkyl linking group.
As an example, Gadekar in U.S. Pat. No. 3,252,986 discloses a series of tranquilizers-muscle relaxants including compounds of formula 5. ##STR6##
Similarly, Wright and Tomcufcik describe a series of pyridinyl benzamides of formula 6 disclosed as cardioprotective agents and inhibitors of thromboxane synthetase. In 6, R is hydrogen, alkyl, ##STR7## alkoxy, or nitro; and n is 2 to 5.
Kruger, et al. in U.S. Pat. No. 4,093,734 disclose a subset of pyridinyl benzamides of formula 7 described as being useful anxiolytics, anticonvulsants, antiemetics, and antiulceragenics. ##STR8##
In 7, R.sup.1 is hydrogen or halogen and R.sup.2 is methyl, halogen or nitro.
Of less significance are disclosures of metaclopramide-type benzamide derivatives having antiemetic and gastroprokinetic properties. Monkovic, et al., are typical in disclosing a series of antiemetic tri-substituted benzamides, 8, in which ##STR9## R.sup.1 is a basic moiety such as --CH.sub.2).sub.n --NR.sup.7 R.sup.8 or ##STR10##
These foregoing references do not teach or suggest the specific novel pyridinyl tri-substituted benzamide derivatives of the present invention nor the anticonvulsant use of these compounds.